Novel Mechanisms of Mammary Oncogenesis by Human Adenovirus Type 9.
Annual rept. 14 Jul 98-13 Jul 99
BAYLOR COLL OF MEDICINE HOUSTON TX
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The adenovirus E4 region-encoded open reading frame 1 9ORF1 transforming protein is the major oncogenic determinant of human adenovirus type 9 Ad9, a virus that generates exclusively estrogen-dependent mammary tumors in rats. Our previous studies demonstrated that 9ORF1 possesses a PDZ domain-binding motif and that disruption of this motif abolishes 9ORF1 transforming activity. PDZ domains are protein-protein interaction modules found in certain cell signaling proteins that localize to specialized membrane sites in cells. Consistent with these observations, we have now identified four different cellular PDZ-domain proteins that complex with 9ORF1 in cells. The fact that three of four 9ORF1-associated PDZ-domain proteins are common targets for high-risk papillomavirus E6 oncoproteins provides further support for the idea that interaction of 9ORF1 with these cellular factors contributes to transformation. Finally, we present results showing that 9ORF1 transforms cells, in part, by activating the phosphoinositide 3-kinase PI 3-Kprotein kinase B PKB signaling pathway. Significantly, our results with 9ORF1 mutant proteins indicate that this important activity depends on the ability of 9ORF1 to complex with the cellular PDZ-domain proteins. It is hoped that these studies will reveal new mechanisms involved in the development of some types of breast tumors in women.
- Anatomy and Physiology
- Medicine and Medical Research